The mandibular condylar cartilage plays a central role in craniofacial disorders, such as mandibular growth abnormalities (micrognathia or prognathia) and temporomandibular joint (TMJ) degeneration, which afflict over 50 million Americans. The mandibular condylar cartilage differs from other articular cartilages in that it undergoes endochondral ossification and robustly remodels, during growth, to mechanical loading cues. However, similar to other joints, the TMJ degenerates with age. Women between the ages 44-55 are the most likely to seek treatment for TMJ degenerative diseases, suggesting a role of estrogen in the disease process. In long bones, estrogen receptor (ER) signaling has been extensively studied and characterized in mediating endochondral growth plate fusion. In contrast, little is known about the role of ER signaling in regulating endochondral mandibular condylar cartilage growth. Our long term goal is to determine the molecular mechanisms regulating mandibular condylar growth and differentiation. The goal of the project is to examine the role of ER alpha and ER beta. Our central hypothesis for this application is that estrogen via ER alpha and ER beta cause cessation of mandibular condylar growth, thereby accelerating age-related TMJ degeneration. To test our hypothesis, we propose the following Specific Aims: Aim 1- Delineate the estrogen receptor signaling pathways that regulate mandibular condylar growth- Our hypothesis for this aim is that estrogen via an ER alpha-sost pathway promotes chondrogenesis and estrogen via an ER beta-tieg1 pathway promotes proliferative pool exit causing cessation of growth. The role of ER alpha, Tieg1 and ER beta in regulating mandibular condylar cartilage growth will be evaluated by altering the estrogen levels in Tieg1 Knockout (KO), ER alpha KO, ER beta KO and Double ER alpha/beta KO mice and examining their mandibular condylar cartilage phenotype and maturation. Aim2- Determine the effects of estrogen signaling on progenitor cell depletion and degeneration -Our hypothesis for this aim is that estrogen via ER alpha and ER beta promote progenitor cell depletion, thereby inhibiting mechanical loading induced TMJ remodeling and accelerating age related TMJ degeneration. In order to examine this mandibular condylar cartilage cell differentiation potential, the anabolic response to mechanical loading induced remodeling and TMJ degeneration in adult and elderly ER alpha KO, ER beta KO and ER alpha/beta DKO mice will be evaluated. We believe that our proposed experiments will help reveal why temporomandibular joint degeneration predominantly afflicts women between the ages of 44-55, and also lead to new approaches to treat mandibular condylar growth abnormalities.